Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis leading to destruction of joints and, sometimes, to severe systemic complications such as vasculitis, amyloidosis or Felty's syndrome. It is widely accepted that a strong genetic component contributes to the susceptibility or resistance to certain human autoimmune diseases such as RA. Attempts to identify the particular genes involved in these disorders has been an area of major focus for many laboratories. Among the numerous genes studied, those encoding the class I and class II molecules of the human leukocyte antigen (HLA) complex have garnered particular attention. The primary function of HLA-class I and class II molecules is binding and presentation of processed antigenic peptides to T cells bearing receptors specific for particular HLA-peptide complexes. The presentation event plays a pivotal role in shaping the cellular immune repertoire and in shaping the nature and scope of the immune response against a given antigen.
In Caucasians, genetic studies initially showed a high prevalence of certain HLA DR subtypes among RA patients. Specifically, predisposition to RA has been linked to the class 30 II HLA-DRB1 locus, and in particular to the DR4 specificity. Within the HLA-DR4 specificity, the Dw4 (DRB1*0401), Dw14 (DRB1*0404/0408), and Dw15 (DRB1*0405) subtypes confer genetic predisposition to RA, while the Dw10 (DRB1*0402) subtype does not confer such genetic predisposition. Nepom et al., Ann. Rev. Immunol. 9: 493-525 (1991); Wordsworth et al., Proc. Natl. Acad. Sci. USA 86: 10049-53 (1989); Ollier et al., Rheum. Dis. Clin. North. Am. 18: 741-59 (1992). Several studies have also shown that the incidence of RA is significantly decreased in patients expressing HLA-DR2 alleles compared with normal controls. Jaraquemada et al., Ann. Rheum. Dis. 45: 627-36 (1986); Deighton et al., Br. J. Rheumatol. 32: 893-98 (1993); Ollier et al., cited supra. Indeed, the DR2Dw12 subtype is associated with a low incidence of RA in the Japanese population. Ohta et al., Human Immunol. 5: 123-32 (1982). For a general review of HLA nomenclature, see Bodmer et al., Tissue Antigens 44: 1-18 (1994), incorporated herein by reference.
DNA sequence analysis revealed that allelic DR4 molecules mainly differ in their third hypervariable (HV3) regions. On this basis, Gregersen et al. proposed, in their "Shared Epitope" hypothesis, that sequence homologies within the HV3 regions of the RA-associated HLA-DRB1 alleles are the molecular basis for RA predisposition. Gregersen et al., Arthritis Rheum. 30: 1205-13 (1987); Winchester et al., Rheum. Dis. Clin, North, Am. 18: 761-83 (1992). In addition, the associations of Dw1 and Dw20 (DRB1*0101/0102) in several ethnic groups and Dw16 (DRB1*1402) in American Indians of the Yakima Nation with RA susceptibility further support the "Shared Epitope" hypothesis. Ollier et al., cited supra; Gregersen et al., cited supra; Winchester et al., cited supra; Willkens et al., Arthritis Rheum. 34: 43-7 (1991). However, associations of RA with DRB1*0301, DRB1*09011, or DRB1*1001 in Arabs, Chileans and Spaniards, respectively, do not fit this model. Ollier et al., cited supra; see also Harris, Ann. Intern. Med. 123: 232-33 (1995). Thus, the precise role of the "Shared Epitope" in RA susceptibility remains unknown.
A further caveat regarding studies aimed at identifying the precise HLA-D region gene responsible for susceptibility to RA is the presence of certain DQB alleles in linkage disequilibrium with particular HLA-DR genes. Such linkages further constrain any conclusions concerning the relative impact of particular HLA-D region genes on RA susceptibility. For example, two allelic forms of DQB, HLA-DQ7 and HLA-DQ8, are associated with the HLA-DR4 genotype in RA susceptibility. Gregersen et al., cited supra; Singal et al., Lancet 2: 1118-20 (1987); Lanchbury et al., Human Immunol. 26: 59-71 (1989). Moreover, an interesting, albeit small, study analyzing Indian patients with RA showed that 100% possessed the HLA-DQ8 allele, versus 33.3% for the normal subjects. Taneja, Rheumatol. Int. 11: 251-55 (1992). Thus, despite an association of the "Shared Epitope" with RA susceptibility, prior studies have also pointed to a possible role for HLA-DQ alleles in this disease.
Collagen-induced arthritis (CIA) is an experimental model of autoimmune polyarthritis that has numerous similarities to human RA. David, APMIS 98: 575-84 (1990). The histopathologic lesions of CIA resemble those seen in RA with synovial proliferation that progresses to pannus formation, with subsequent marginal bone erosions and cartilage destruction. Radiographs of joints affected by CIA often show erosive changes similar to those seen in human RA, and progressive arthritis often results in joint deformity and destruction similar to that seen with RA. As in some patients with human RA, anti-collagen antibodies develop in the CIA model.
In the CIA model, mice are injected intradermally with either homologous or heterologous species type II collagen with complete or incomplete Freund's adjuvant. During the first two weeks after immunization, the immune response is detected by the presence of delayed type hypersensitivity (DTH) to type II collagen as measured by skin test or ear thickness measurements. The DTH response peaks at day 10 after injection. Antibodies to type II collagen are detected in the peripheral blood 2 weeks after injection and IgG peak titers are reached at about 4 weeks. X-ray evidence of joint involvement is apparent by 4-6 weeks with the onset of clinically apparent arthritis by 7-9 weeks.
In mice, studies using congenic and recombinant mice have narrowed down the gene(s) controlling CIA susceptibility to the MHC class H-2A molecules, such that only mice with the H-2.sup.q, H-2.sup.r, H-2.sup.w3 or H-2.sup.w17 haplotypes are susceptible to the disease. Wooley et al., J. Exp. Med. 154: 688-700 (1981); Wooley et al., Transplant. Proc. 157: 180-85 (1983); Holmdahl et al., Proc. natl. Acad. Sci. USA 86: 9475-79 (1989). Presentation of the Type II collagen (CII) peptide 250-270 by the H-2A.sup.q molecule is probably the most important event in disease induction. Myers et al., J. Immunol. 151: 500-05 (1993). In q, w3 and w17 haplotypes, the H-2E molecule is not functional because of mutations in both the Ea and Eb genes. Begovich et al., J. Immunol. 144: 1957-64 (1990).
Thus, while human RA is associated with polymorphisms in the HLA-DRB1 locus (mouse H-2Eb equivalent), mouse CIA is associated with polymorphisms in the H-2Ab locus (human DQB1 equivalent). This presents a paradox of sorts, since to date all of the major functions of the major histocompatibility genes in humans and mice have been found to be substantially similar between equivalent regions. Resolution of this paradox would allow development of animal (e.g., mouse) models permitting identification and testing of agents for prevention and treatment of rheumatoid arthritis in humans.